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Solli E, Doshi H, Elze T, Pasquale LR, Branco J, Wall M, Kupersmith M. Archetypal analysis of visual fields in optic neuritis reveals functional biomarkers associated with outcome and treatment response. Mult Scler Relat Disord 2022;67:104074.Abstract
BACKGROUND AND OBJECTIVES: Archetypal analysis (AA), a form of unsupervised machine learning, can identify quantifiable visual field (VF) patterns seen in optic neuritis (ON), known as archetypes (ATs). We hypothesized that AT weight changes over time would reflect the course of recovery and the effects of therapy in ON. We explored whether baseline AT weights would be associated with VF status at the clinical trial outcome and if ATs would indicate residual VF defects in eyes with mean deviation (MD) ≥ -2.00 at six months. METHODS: We used a published 16-AT model derived from 3892 Optic Neuritis Treatment Trial VFs (456 eyes) for all analyses. We measured AT weight changes over the six-month study period and used asymptotic regression to analyze the rate of change. We compared AT weights at six months between treatment groups. We evaluated associations between baseline AT weight thresholds and VF outcome or treatment effect. We calculated residual AT weights in eyes with MD ≥ -2.00 dB at six months. RESULTS: Over six months, AT1 (a normal VF pattern) demonstrated the greatest median weight change, increasing from 0.00% (IQR 0.00-0.00%) at baseline to 60.0% (IQR 38.3-70.8%) at six months (p < 0.001). At outcome, the intravenous methylprednisolone (IVMP) group had the highest median AT1 weight (IVMP: 63.3%, IQR 51.3-72.8%; placebo: 56.2%, IQR 35.1-71.6%; prednisone 58.3%, IQR 35.1-71.6%; p = 0.019). Eyes with AT1 weight ≥ 19% at baseline had superior median MD values (-0.91 vs. -2.07 dB, p < 0.001) and AT1 weights (70.8% vs. 57.8% p < 0.001) at six months. Only eyes with AT1 weight < 19% at baseline showed a treatment benefit for IVMP, with a higher six-month median AT1 weight compared to placebo (p = 0.015) and prednisone (p = 0.016), and a higher median MD compared to placebo (p = 0.027). At six months, 182 (80.2%) VFs with MD ≥ -2.00 had at least one abnormal AT. DISCUSSION: Changes in quantifiable, archetypal patterns of VF loss reflect recovery in ON. Machine learning analysis of the VFs in optic neuritis reveals associations with response to therapy and VF outcome, and uncovers residual deficits, not readily seen with standard evaluations.
Gholizadeh S, Chen X, Yung A, Naderi A, Ghovvati M, Liu Y, Farzad A, Mostafavi A, Dana R, Annabi N. Development and optimization of an ocular hydrogel adhesive patch using definitive screening design (DSD). Biomater Sci 2022;Abstract
Adhesive hydrogels based on chemically modified photocrosslinkable polymers with specific physicochemical properties are frequently utilized for sealing wounds or incisions. These adhesive hydrogels offer tunable characteristics such as tailorable tissue adhesion, mechanical properties, swelling ratios, and enzymatic degradability. In this study, we developed and optimized a photocrosslinkable adhesive patch, GelPatch, with high burst pressure, minimal swelling, and specific mechanical properties for application as an ocular (sclera and subconjunctival) tissue adhesive. To achieve this, we formulated a series of hydrogel patches composed of different polymers with various levels of methacrylation, molecular weights, and hydrophobic/hydrophilic properties. A computerized multifactorial definitive screening design (DSD) analysis was performed to identify the most prominent components impacting critical response parameters such as adhesion, swelling ratio, elastic modulus, and second order interactions between applied components. These parameters were mathematically processed to generate a predictive model that identifies the linear and non-linear correlations between these factors. In conclusion, an optimized formulation of GelPatch was selected based on two modified polymers: gelatin methacryloyl (GelMA) and glycidyl methacrylated hyaluronic acid (HAGM). The ex vivo results confirmed adhesion and retention of the optimized hydrogel subconjunctivally and on the sclera for up to 4 days. The developed formulation has potential to be used as an ocular sealant for quick repair of laceration type ocular injuries.
Maleki A, Philip A, Foster SC. Adalimumab Monotherapy in the Treatment of Idiopathic Multifocal Choroiditis: A Case Report. Case Rep Ophthalmol 2022;13(3):793.Abstract
In this study, we report a case of multifocal choroiditis that was successfully treated with adalimumab monotherapy. A 25-year-old male presented with a history of bilateral multifocal choroiditis which was resistant to a combination of azathioprine, valacyclovir, and prednisone. Dilated fundoscopy revealed small creamy-yellow lesions around the arcades in both eyes (OU). Indocyanine green angiography (ICGA) revealed active hypocyanescent lesions around the arcades and macula OU. Valacyclovir was stopped, adalimumab subcutaneous injections biweekly were added to the regimen, and prednisone was tapered after the second adalimumab loading dose. At 3-month follow-up, ocular examination and ICGA were unremarkable OU. After 30 months of remission, azathioprine was tapered and stopped. After 40 months of remission, adalimumab was tapered and stopped. Four months after stopping adalimumab injections, the patient returned with new floaters in his right eye (OD). ICGA and macular optical coherence tomography detected active lesions OU. The patient was restarted on adalimumab subcutaneous injections as monotherapy. At 3-month follow-up visit, his symptoms had resolved, and ICGA showed resolution of the lesions OD and improvement of the lesions in the left eye (OS). He has been in remission for 6 months at the time of writing since restarting adalimumab monotherapy. We conclude from this study that long-term adalimumab monotherapy can be employed effectively and safely in the re-treatment of patients with multifocal choroiditis resistant to other immunomodulatory therapy even after successful tapering and discontinuation of concurrent therapies.
Pitts KM, Neeson CE, Hall NE, Lin JB, Falah HK, Wang SL, Lo KT, Song CE, Margeta MA, Solá-Del Valle DA. Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma. Transl Vis Sci Technol 2022;11(11):1.Abstract
PURPOSE: Galectin-3 (Gal-3) and apolipoprotein E (APOE) are markers of activated microglia in neurodegenerative diseases of the central nervous system, whose targeting is protective in mouse models of glaucoma. In this study, we examined levels of Gal-3 and APOE in human aqueous humor (AH) and defined their clinical associations with glaucoma. METHODS: We collected AH from 59 glaucoma patients and 15 controls at the start of planned ophthalmic surgery. Gal-3 and APOE levels were quantified by enzyme-linked immunosorbent assay. Total protein in AH was quantified by bicinchoninic acid assay. Significant associations between Gal-3, APOE, and clinical covariates were defined using univariate and multivariate linear regression models. RESULTS: Gal-3 and APOE levels were significantly elevated in the AH of glaucoma patients compared to controls (P = 0.004 and P < 0.001, respectively). Gal-3 and APOE were positively correlated across the entire cohort (r = 0.65, P = 6.2E-9). No association was observed between Gal-3 and total protein or APOE and total protein (P = 0.35 and P = 0.50, respectively), indicating that their levels were not increased in glaucomatous AH due to nonspecific protein accumulation. Multivariate linear regression modeling revealed significant associations between Gal-3 and maximum recorded intraocular pressure (P = 0.009) and between APOE and number of past ophthalmic surgeries (P = 0.031). CONCLUSIONS: We demonstrate that Gal-3 and APOE are significantly elevated in the AH of eyes with glaucoma and are associated with a history of poorly controlled disease. TRANSLATIONAL RELEVANCE: Gal-3 and APOE in AH may inform clinical decision-making as quantifiable readouts of microglial activation in eyes with glaucoma.
Kaufman AR, Chodosh J, Pineda R. Monkeypox Virus and Ophthalmology-A Primer on the 2022 Monkeypox Outbreak and Monkeypox-Related Ophthalmic Disease. JAMA Ophthalmol 2022;Abstract
IMPORTANCE: An ongoing global monkeypox virus outbreak in 2022 includes the US and other nonendemic countries. Monkeypox ophthalmic manifestations may present to the ophthalmologist, or the ophthalmologist may be involved in comanagement. This narrative review creates a primer for the ophthalmologist of clinically relevant information regarding monkeypox, its ophthalmic manifestations, and the 2022 outbreak. OBSERVATIONS: Monkeypox virus is an Orthopoxvirus (genus includes variola [smallpox] and vaccinia [smallpox vaccine]). The 2022 outbreak is of clade II (historically named West African clade), specifically subclade IIb. In addition to historic transmission patterns (skin lesions, bodily fluids, respiratory droplets), sexual transmission has also been theorized in the current outbreak due to disproportionate occurrence in men who have sex with men. Monkeypox causes a characteristic skin eruption and mucosal lesions and may cause ophthalmic disease. Monkeypox-related ophthalmic disease (MPXROD) includes a spectrum of ocular pathologies including eyelid/periorbital skin lesions, blepharoconjunctivitis, and keratitis). Smallpox vaccination may reduce MPXROD occurrence. MPXROD seems to be rarer in the 2022 outbreaks than in historical outbreaks. MPXROD may result in corneal scarring and blindness. Historical management strategies for MPXROD include lubrication and prevention/management of bacterial superinfection in monkeypox keratitis. Case reports and in vitro data for trifluridine in other orthopoxviruses suggest a possible role for MPXROD. Tecovirimat, cidofovoir, brincidofovir and vaccinia immune globulin intravenous may be used for systemic infection. There is a theoretical risk for monkeypox transmission by corneal transplantation, and the Eye Bank Association of America has provided guidance. Smallpox vaccines (JYNNEOS [Bavarian Nordic] and ACAM2000 [Emergent Product Development Gaithersburg Inc]) provide immunity against monkeypox. CONCLUSIONS AND RELEVANCE: The ophthalmologist may play an important role in the diagnosis and management of monkeypox. MPXROD may be associated with severe ocular and visual morbidity. As the current outbreak evolves, up-to-date guidance from public health organizations and professional societies are critical.
Patel NA, Al-Khersan H, Yannuzzi NA, Lin J, Smiddy WE. Aflibercept Monotherapy versus Bevacizumab First for Diabetic Macular Edema: A Cost Analysis based on DRCR Protocol AC Results. Ophthalmol Retina 2022;Abstract
PURPOSE: To calculate costs of treatment for diabetic macular edema (CI-DME) with bevacizumab-first (step therapy) compared to aflibercept monotherapy. DESIGN: Cost analysis of treatment arms based on a published study SUBJECTS: None METHODS: Published results from the Diabetic Retinopathy Clinical Research Network (DRCR.net) protocol AC were used to assess costs. Data incorporated in a usage and outcome model included frequency of injections, medication type, visits, and imaging. Costs were modeled based on 2022 Medicare reimbursement data for both facility (hospital-based) and non-facility settings in Miami. Outcomes were similar in Protocol AC so were not differentially studied. Results were extrapolated so as to estimate lifetime (17 years for the age of the cohort). RESULTS: Over the 2 years reported in protocol AC, the cost required to treat in the facility (nonfacility setting) was $42,000 ($32,000) in the aflibercept monotherapy group and $29,000 ($22,000) in the bevacizumab-first group. Extrapolated modeled lifetime costs were $158,000 ($136,000) and $125,000 ($103,000), respectively. The total cost with bevacizumab-first was 33% lower at year 2 and 21% lower at year 17 compared with aflibercept monotherapy. Savings per year for the 2 year results were $6,500 ($5000) in the facility (non-facility) setting. For the extrapolated 17 year model annual savings were $1900 ($1900) in the facility (non-facility) setting. The professional fees accounted for a minority of overall costs; in contrast, medication costs accounted for 82% of the total costs for the aflibercept monotherapy and 73% in the bevacizumab-first group at 2 years. Our model predicted an additional 15% lifetime cumulative savings if patients still not meeting threshold criteria after switching to aflibercept were placed back on bevacizumab, and a similar degree of improvement if those on not meeting threshold criteria on aflibercept monotherapy were switched to bevacizumab. MAIN OUTCOME MEASURES: Cost of treatment options. CONCLUSION: Medication is the dominant driver of the total expenses associated with the treatment of diabetic macular edema. While cost savings are realized with bevacizumab-first step therapy, the magnitude was not as much as might be intuited, probably due to the high (70%) incidence of patients switching to aflibercept within Protocol AC.
Sharifi S, Sharifi H. Electrospun-Reinforced Suturable Biodegradable Artificial Cornea. ACS Appl Bio Mater 2022;Abstract
Despite rigorous investigations, the hydrogels currently available to replace damaged tissues, such as the cornea, cannot fulfill mechanical and structural requirements and, more importantly, cannot be sutured into host tissues due to the lack of hierarchical structures to dissipate exerted stress. In this report, solution electrospinning of polycaprolactone (PCL), protein-based hydrogel perfusion, and layer-by-layer stacking are used to generate a hydrogel-microfiber composite with varying PCL fiber diameters and hydrogel concentrations. Integrating PCL microfibers into the hydrogel synergistically improves the mechanical properties and suturability of the construct up to 10-fold and 50-fold, respectively, compared to the hydrogel and microfiber scaffolds alone, approaching those of the corneal tissue. Human corneal cells cultured on composites are viable and can spread, proliferate, and retain phenotypic characteristics. Moreover, corneal stromal cells migrate into the scaffold, degrade it, and regenerate the extracellular matrix. The current hydrogel reinforcing system paves the way for producing suturable and, therefore, transplantable tissue constructs with desired mechanical properties.
Bleicher ID, Tainsh LT, Gaier ED, Armstrong GW. Outcomes of Zone 3 Open Globe Injuries By Wound Extent Subcategorization of zone 3 injuries segregates visual and anatomic outcomes. Ophthalmology 2022;Abstract
PURPOSE: Open globe injuries (OGIs) are categorized by zone, with Zone 3 (Z3) comprising wounds >5mm beyond the limbus. Outcomes of Z3 OGIs are highly heterogenous. OGIs with far posterior wounds (pZ3) were hypothesized to have worse visual and anatomic outcomes. DESIGN: Single-center retrospective cohort study PARTICIPANTS: 258 eyes with zone 3 open globe injuries METHODS: A retrospective review of Z3 OGIs treated at a tertiary center over 12 years. Wounds ≥10mm posterior to the limbus were defined as pZ3. Outcomes were compared between pZ3 and anterior Z3 (aZ3) eyes. MAIN OUTCOME MEASURES: Visual acuity on a logMAR scale. Secondary outcomes included anatomic outcomes, development of retinal detachment (RD) and proliferative vitreoretinopathy (PVR), and number of secondary surgeries. RESULTS: A total of 258 Z3 OGI eyes with >30 days follow-up were assessed; 161 (62%) were pZ3. At 3 month follow-up, pZ3 OGIs were more likely to exhibit NLP (pZ3: 38%; aZ3: 17%; p<0.003), lack count fingers vision (pZ3: 72%; aZ3: 43%; p<0.002) and fail to read a letter on the eye chart (pZ3: 83%; aZ3: 64%; p<0.001). The visual acuity distribution at 3 months was significantly worse for pZ3 compared to aZ3 injuries (p<0.004). Similar results were found at final follow-up. Multiple linear regression showed that pZ3 location was independently associated with worse visual acuity (β 0.29, 95% CI: 0.09-0.50, p<0.006) in addition to presenting acuity, age, vitreous hemorrhage, uveal prolapse and afferent pupillary defect. pZ3 injuries were more likely to develop RDs (pZ3: 87%; aZ3: 71%; p<0.01) and PVR (pZ3 66%; aZ3 47%; p<0.03). Patients with pZ3 OGIs were significantly more likely to reach a poor anatomic outcome (phthisis, enucleation, need for keratoprosthesis) compared with aZ3 OGI patients (pZ3: 56%; aZ3: 40%; p<0.03). CONCLUSION: Posterior OGI extension independently portends worse visual and anatomic outcomes. The effect on visual outcome was durable and clinically relevant compared with established predictors of OGI outcomes. Application of these findings improve prognostic precision and will guide future research efforts to optimize surgical decision-making in severe OGI cases.
Liang YB, Shen R, Zhou W, Fan S, Chan PP, Tham CCY, Congdon N, Friedman DS, Wang N. Prevalence and Ocular Biometric Characteristics of Myopia in Primary Angle Closure Disease in Rural China: The Handan Eye Study. Invest Ophthalmol Vis Sci 2022;63(12):19.Abstract
PURPOSE: The purpose of this study was to determine the prevalence of myopia among patients with primary angle closure disease (PACD) in rural China and their ocular biometric characteristics. METHODS: Study subjects were recruited from the Handan Eye Study. A/B-mode scan (Cine Scan, Quantel Medical, Cedex, France) was used to measure the axial length, anterior chamber depth (ACD), and lens thickness (LT). PACD was defined as the anterior chamber angle being considered closed when 180 degrees or more of the posterior pigmented trabecular meshwork were not visible on the gonioscopy. Myopia was defined as a spherical equivalent (SE) refractive error ≤-0.5 diopter (D). Persons who did not meet PACD definition were classified as the open-angle (OA) group. RESULTS: The overall prevalence of myopia in persons with PACD was 13.7% (11.6% in primary angle closure suspect [PACS], 21.6% in primary angle closure [PAC], 62.5% in primary angle closure glaucoma [PACG]). The age-specific prevalence of myopia in PACD eyes was 41.7% at 30 to 39 years old, 12.3% at 40 to 49 years old, 8.7% at 50 to 59 years old, 10.7% at 60 to 69 years old, and 31.7% at age 70 years and over. PACD had shorter AL (22.2 ± 0.8 vs. 22.9 ± 0.9 mm, P < 0.001), shallower ACD (2.3 ± 0.3 vs. 2.8 ± 0.4 mm, P < 0.001), and greater LT (5.0 ± 0.5 vs. 4.7 ± 0.5 mm, P < 0.001). PACD had even thicker lenses and deeper ACD with age than those with OA (all P ≤ 0.025) from 30 years to 70 years of age and over. CONCLUSIONS: Myopia was common among persons with PACD who were less than 40 years of age in this rural Chinese population, and over half of those with PACG were myopic.
Keel S, Lingham G, Misra N, Block S, Bourne R, Calonge M, Cheng C-Y, Friedman DS, Furtado JM, Khanna R, Mariotti S, Mathenge W, Matoto E, Müeller A, Rabiu M, Rasengane T, Resnikoff S, Wormald R, Yasmin S, Zhao J, Evans JR, Cieza A, of Group PECID. Toward Universal Eye Health Coverage-Key Outcomes of the World Health Organization Package of Eye Care Interventions: A Systematic Review. JAMA Ophthalmol 2022;Abstract
IMPORTANCE: Despite persistent inequalities in access to eye care services globally, guidance on a set of recommended, evidence-based eye care interventions to support country health care planning has not been available. To overcome this barrier, the World Health Organization (WHO) Package of Eye Care Interventions (PECI) has been developed. OBJECTIVE: To describe the key outcomes of the PECI development. EVIDENCE REVIEW: A standardized stepwise approach that included the following stages: (1) selection of priority eye conditions by an expert panel after reviewing epidemiological evidence and health facility data; (2) identification of interventions and related evidence for the selected eye conditions from a systematic review of clinical practice guidelines (CPGs); stage 2 included a systematic literature search, screening of title and abstracts (excluding articles that were not relevant CPGs), full-text review to assess disclosure of conflicts of interest and affiliations, quality appraisal, and data extraction; (3) expert review of the evidence extracted in stage 2, identification of missed interventions, and agreement on the inclusion of essential interventions suitable for implementation in low- and middle-income resource settings; and (4) peer review. FINDINGS: Fifteen priority eye conditions were chosen. The literature search identified 3601 articles. Of these, 469 passed title and abstract screening, 151 passed full-text screening, 98 passed quality appraisal, and 87 were selected for data extraction. Little evidence (≤1 CPG identified) was available for pterygium, keratoconus, congenital eyelid disorders, vision rehabilitation, myopic macular degeneration, ptosis, entropion, and ectropion. In stage 3, domain-specific expert groups voted to include 135 interventions (57%) of a potential 235 interventions collated from stage 2. After synthesis across all interventions and eye conditions, 64 interventions (13 health promotion and education, 6 screening and prevention, 38 treatment, and 7 rehabilitation) were included in the PECI. CONCLUSIONS AND RELEVANCE: This systematic review of CPGs for priority eye conditions, followed by an expert consensus procedure, identified 64 essential, evidence-based, eye care interventions that are required to achieve universal eye health coverage. The review identified some important gaps, including a paucity of high-quality, English-language CPGs, for several eye diseases and a dearth of evidence-based recommendations on eye health promotion and prevention within existing CPGs.
Farhat W, Yeung V, Kahale F, Parekh M, Cortinas J, Chen L, Ross AE, Ciolino JB. Doxorubicin-Loaded Extracellular Vesicles Enhance Tumor Cell Death in Retinoblastoma. Bioengineering (Basel) 2022;9(11)Abstract
Chemotherapy is often used to treat retinoblastoma; however, this treatment method has severe systemic adverse effects and inadequate therapeutic effectiveness. Extracellular vesicles (EVs) are important biological information carriers that mediate local and systemic cell-to-cell communication under healthy and pathological settings. These endogenous vesicles have been identified as important drug delivery vehicles for a variety of therapeutic payloads, including doxorubicin (Dox), with significant benefits over traditional techniques. In this work, EVs were employed as natural drug delivery nanoparticles to load Dox for targeted delivery to retinoblastoma human cell lines (Y-79). Two sub-types of EVs were produced from distinct breast cancer cell lines (4T1 and SKBR3) that express a marker that selectively interacts with retinoblastoma cells and were loaded with Dox, utilizing the cells' endogenous loading machinery. In vitro, we observed that delivering Dox with both EVs increased cytotoxicity while dramatically lowering the dosage of the drug. Dox-loaded EVs, on the other hand, inhibited cancer cell growth by activating caspase-3/7. Direct interaction of EV membrane moieties with retinoblastoma cell surface receptors resulted in an effective drug delivery to cancer cells. Our findings emphasize the intriguing potential of EVs as optimum methods for delivering Dox to retinoblastoma.
Galli J, Loi E, Strobio C, Micheletti S, Martelli P, Merabet LB, Pasini N, Semeraro F, Fazzi E, Fazzi E. Neurovisual profile in children affected by Angelman syndrome. Brain Dev 2022;Abstract
BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder caused by altered expression of the maternal copy of the UBE3A gene. Together with motor, cognitive, and speech impairment, ophthalmological findings including strabismus, and ocular fundus hypopigmentation characterize the clinical phenotype. The aim of this study was to detail the neurovisual profile of children affected by AS and to explore any possible genotype-phenotype correlations. METHODS: Thirty-seven children (23 females, mean age 102.8 ± 54.4 months, age range 22 to 251 months) with molecular confirmed diagnosis of AS were enrolled in the study. All underwent a comprehensive video-recorded neurovisual evaluation including the assessment of ophthalmological aspects, oculomotor functions, and basic visual abilities. RESULTS: All children had visual impairments mainly characterized by refractive errors, ocular fundus changes, strabismus, discontinuous/jerky smooth pursuit and altered saccadic movements, and/or reduced visual acuity. Comparing the neurovisual profiles between the deletion and non-deletion genetic subgroups, we found a significant statistical correlation between genotype and ocular fundus hypopigmentation (p = 0.03), discontinuous smooth pursuit (p < 0.05), and contrast sensitivity abnormalities (p < 0.01) being more frequent in the deletion subgroup. CONCLUSIONS: Subjects affected by AS present a wide spectrum of neurovisual impairments that lead to a clinical profile consistent with cerebral visual impairment (CVI). Moreover, subjects with a chromosome deletion show a more severe visual phenotype with respect to ocular fundus changes, smooth pursuit movements, and contrast sensitivity. Early detection of these impaired visual functions may help promote the introduction of neurovisual habilitative programs which can improve children's visual, neuromotor, and cognitive outcomes.

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